The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population

Hsin Chou Yang; Chih Min Liu; Yu Li Liu; Chia Wei Chen; Chien Ching Chang; Cathy S.J. Fann; Jen Jie Chiou; Ueng Cheng Yang; Chun Houh Chen; Stephen V. Faraone; Ming T. Tsuang; Hai Gwo Hwu

doi:10.1371/journal.pone.0060099

The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population

Hsin Chou Yang, Chih Min Liu, Yu Li Liu, Chia Wei Chen, Chien Ching Chang, Cathy S.J. Fann, Jen Jie Chiou, Ueng Cheng Yang, Chun Houh Chen, Stephen V. Faraone, Ming T. Tsuang, Hai Gwo Hwu^*

^*Corresponding author for this work

Institute of Biomedical Informatics

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Background: Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. Methods: We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. Results: We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1, DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. Conclusions: These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.

Original language	English
Article number	e60099
Journal	PLoS ONE
Volume	8
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0060099
State	Published - 28 Mar 2013

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@article{46cc95c3497442ef865367f2b6b78bc4,

title = "The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population",

abstract = "Background: Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. Methods: We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. Results: We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1, DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. Conclusions: These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.",

author = "Yang, {Hsin Chou} and Liu, {Chih Min} and Liu, {Yu Li} and Chen, {Chia Wei} and Chang, {Chien Ching} and Fann, {Cathy S.J.} and Chiou, {Jen Jie} and Yang, {Ueng Cheng} and Chen, {Chun Houh} and Faraone, {Stephen V.} and Tsuang, {Ming T.} and Hwu, {Hai Gwo}",

note = "Funding Information: We gratefully acknowledge the sequencing work performed by the National Sequencing Core Facility in National Yang-Ming University, the bioinformatics analysis performed by the Bioinformatics Consortium of Taiwan core facility, and the SNP genotyping performed by the National Center for Genome Medicine within the National Science Council in Taiwan. We also acknowledge the assistance provided by the Microarray and SNP Core Facility for Genomic Medicine at National Taiwan University Hospital.",

year = "2013",

month = mar,

day = "28",

doi = "10.1371/journal.pone.0060099",

language = "English",

volume = "8",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

}

TY - JOUR

T1 - The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population

AU - Yang, Hsin Chou

AU - Liu, Chih Min

AU - Liu, Yu Li

AU - Chen, Chia Wei

AU - Chang, Chien Ching

AU - Fann, Cathy S.J.

AU - Chiou, Jen Jie

AU - Yang, Ueng Cheng

AU - Chen, Chun Houh

AU - Faraone, Stephen V.

AU - Tsuang, Ming T.

AU - Hwu, Hai Gwo

N1 - Funding Information: We gratefully acknowledge the sequencing work performed by the National Sequencing Core Facility in National Yang-Ming University, the bioinformatics analysis performed by the Bioinformatics Consortium of Taiwan core facility, and the SNP genotyping performed by the National Center for Genome Medicine within the National Science Council in Taiwan. We also acknowledge the assistance provided by the Microarray and SNP Core Facility for Genomic Medicine at National Taiwan University Hospital.

PY - 2013/3/28

Y1 - 2013/3/28

N2 - Background: Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. Methods: We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. Results: We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1, DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. Conclusions: These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.

AB - Background: Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment. Methods: We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia. Results: We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1, DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO. Conclusions: These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.

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U2 - 10.1371/journal.pone.0060099

DO - 10.1371/journal.pone.0060099

M3 - Article

C2 - 23555897

AN - SCOPUS:84875523917

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 3

M1 - e60099

ER -

The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population

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